Influenza is a respiratory infection caused by the influenza virus that is prevalent worldwide. One of the most contagious variants of influenza is influenza A virus (IAV), which usually spreads in closed spaces through aerosols. Preventive measures such as novel compounds are needed that can act on viral membranes and provide a safe environment against IAV infection. In this study, we screened compounds with common fragrances that are generally used to mask unpleasant odors but can also exhibit antiviral activity against a strain of IAV. Initially, a set of 188 structurally diverse odorants were collected, and their antiviral activity was measured in vapor phase against the IAV solution. Regression models were built for the prediction of antiviral activity using this set of odorants by taking into account their structural features along with vapor pressure and partition coefficient (n-octanol/water). The models were interpreted using a feature weighting approach and Shapley Additive exPlanations to rationalize the predictions as an additional validation for virtual screening. This model was used to screen odorants from an in-house odorant data set consisting of 2020 odorants, which were later evaluated using in vitro experiments. Out of 11 odorants proposed using the final model, 8 odorants were found to exhibit antiviral activity. The feature interpretation of screened odorants suggested that they contained hydrophilic substructures, such as hydroxyl group, which might contribute to denaturation of proteins on the surface of the virus. These odorants should be explored as a preventive measure in closed spaces to decrease the risk of infections of IAV.
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